The long-term objectives of this work are to improve the understanding of the inhibition of the HIV-integrase (IN) enzyme in order to allow the development of clinical agents targeted against this enzyme for the treatment of HIV and AIDS. This long-term objective will be approached by first examining the interaction of known IN inhibitors with divalent metal cations to test the hypothesis that they interact with such a cation in the active site of IN. This information will be utilized in the QSAR and 3D-QSAR methods that comprise the second specific aim. Such studies will determine common functional groups and properties that lead to activity. The third specific aim of this work is to dock inhibitors into IN in a manner consistent with 3D-QSAR results and know activity data. Interactions between divalent metal cations and IN inhibitors will be calculated using ab initio methods, specifically the 6-311G* basis set with MP2 energy correction. The energies of the divalent metal cation and the inhibitor alone will be subtracted from the energy of the complex to derive the interaction energy. These interaction energies can then be utilized as one descriptor in a QSAR model. QSAR models will be derived using topological and geometric molecular descriptors. The predictive ability of the models will be evaluated using the leave-one-out and leave-set-out cross-validation methods. Docking studies of IN and its inhibitors will be performed using the DOCK and AUTOdock programs. Multiple inhibitors will be docked into the enzyme in order to calculate interaction energies for each. These interaction energies are expected to be correlated with the experimentally determined binding affinities. Specific interactions between the inhibitors and the enzyme will also be examined for consistency with published mutagenesis work. The proposed work will assist in the development of second-generation IN inhibitors that may improve the treatment of HIV and AIDS.